In order to facilitate analysis of the complex immune response to cancer cells, a well-defined tumor model systems have been established in our group. In this model the metastatic mouse breast cancer 4T1.2 or the mouse renal carcinoma Renca have been transfected with the viral protein hemagglutinin (4T1.2-HA, Renca-HA) as a surrogate tumor antigen. The transfer of the viral HA gene provides a tumor that is much more immunogenic, due to response by CD 8 cytotoxic T cells of the mouse to the viral protein. In addition transgenic mice have been generated where the T cell receptor (TCR) transgene specifically recognizes a single dominant peptide of the viral HA protein (TCR-HA), thus allowing for this antigen-specific T cell population to be accurately followed and monitored in vivo. These mice have been crossed onto strains which lack some of the cytotoxic effector molecules of T cells such as perforin and FasL important for killing tumor cells in vitro. Using such a pre-clinical model system we have demonstrated that the proteasome inhibitor bortezomib, when administered a with an optimal dose and timing can be combined with adoptive T cell transfer to improve therapeutic outcome. This seems to be due to both the sensitization of the cancer cells by bortezomib to undergo immune-mediated apoptosis as well as the unexpected enhancement of an ongoing anti-cancer response. More recently we have identified specific members of the withanolide family of natural products that sensitize cancer cells to apoptosis in response to TNF family death ligands. Therefore in current ongoing studies we are assessing if these active withanolides can be combined with adoptive T cell transfer, checkpoint (anti-PD-1) inhibition and immune adjuvant (poly (I:C) therapies in preclinical models of melanoma, renal cancer and breast cancer